2-(2-ethyl lower alkylamino)benzophenone oximes

ABSTRACT

NOVEL 2(2-ETHYL LOWER ALKYLAMINO)-BENZOPHENONE OXIMES ARE DISCLOSED. THESE COMPOUNDS ARE USEFUL AS INTERMEDIATES IN THE PREPARATION OF PHARMACOLOGICALLY ACTIVE 2,3-DIHYDRO-IH-1,4-BENZODIAZEPINES.

United States Patent Oflice 3,803,233. Patented Apr. 9, 1974 U.S. Cl.260-566 A 2 Claims ABSTRACT OF THE DISCLOSURE Novel 2-(2-ethy1 loweralkylamino)-benzophenone oximes are disclosed. These compounds areuseful as intermediates in the preparation of pharmacologically ac tive2,3-dihydro-lH-1,4-benzodiazepines.

The present application is a divisional application of co-pending U.S.patent application Ser. No. 819,410, filed Apr. 25, 1969, and now U.S.Pat. 3,646,011 issued Feb. 29, 1972, which in turn is acontinuation-in-part application of U.S. patent application Ser. No.763,044, filed Sept. 26, 1968, and now U.S. Pat. 3,583,978.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to thepreparation of compounds of the following formula wherein R and R eachare selected from the group consisting of hydrogen, halogen,trifluoromethyl, nitro, amino, lower alkanoylamino, lower alkylthio,lower alkyl sulfonyl, lower alkylsulfinyl, lower alkoxy, hydroxy, loweralkyl, cyano, carboxy, carbo-lower alkoxy, carbamyl, and di-loweralkylamine; and R is selected from the group consisting of hydrogen,lower alkyl, lower alkenyl and lower alkanoyl by, in one embodiment, aprocess wherein a compound of the following formula wherein R R and Rare as above and A is a leaving gIOuP is reacted with hydroxylamine.

As used in this disclosure, the term lower alkyl comprehends bothstraight and branched chain carbon-hydrogen radicals having from 1 to 7,preferably from 1 to 4 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl and the like. The term lower alkenyl includes straightand branched chain carbon-hydrogen radicals having from 1-7, preferablyfrom 1-4 carbon atoms, wherein at least one carbon to carbon bond isunsaturated such as allyl and the like. The term lower alkanoyl includesthe acyl residue of lower alkanoic acids, for example, acetyl,propionyl, and the like. The term halogen encompasses all four halogens,e.g., fluorine, chlorine, bromine and iodine.

In a preferred embodiment of the present invention, compounds of FormulaI above are prepared wherein R, and R are selected from the groupconsisting of hydrogen, halogen trifluoromethyl and nitro and R is loweralkyl. In a more preferred embodiment R is halogen, most preferablychlorine and R is hydrogen. In the most preferred embodiment, R ismethyl, R is substituted at the 7-position of the benzodiazepine ringand R when other than hydrogen is preferably substituted at the 2'-position.

The process for preparing compounds of the Formula I from correspondingcompounds of Formula II above by means of a reaction with hydroxylamineor a salt thereof, e.g., hydroxylamine hydrochloride, may be conductedin various ways. In one preferred embodiment, the reaction betweencompounds of Formula II and hydroxylamine is conducted in a suitablesolvent such as aqueous lower alkanol in the presence of a base such asa carbonate, e.g., potassium or sodium carbonate, or an alkali oralkaline earth hydroxide, etc.

The reaction may also be carried out in excess hydroxylamine whichserves both as solvent and as base in the reaction. Alternatively, thehydroxylamine may be admixed with an organic base, such as pyridine ortriethylamine which serve as solvents and also as added bases. Apreferred embodiment of the present invention utilizes as a reactionmixture hydroxylamine hydrochloride in ethanol to which has been addedpotassium carbonate in water.

The aforesaid reaction for the preparation of compounds of Formula I isgenerally carried out in a temperature range of 0 to the refluxtemperature of the solvent medium. In preferred embodiments theaforesaid reaction is conducted at a temperature in the range of fromroom temperature to the reflux temperature of the solvent medium. Theselection of pressure conditions is not critical to the operation of theprocess of the present invention within normal ranges of pressuresgenerally employed in the laboratory.

The leaving group defined as A encompasses for example leaving groupsnormally employed in the chemical art such as a halogen, e.g., chloro,bromo or iodo substituents, the mesyloxy and tosyloxy groups, etc. In apreferred embodiment, leaving group A is preferably selected from theenumerated halogens and most preferably is chloro.

Compounds of Formula II are most readily prepared from compounds of thefollowing formula (III) wherein R R and R are as above.

via an intermediate compound of the following formula wherein R R and Rare as above.

Compounds of Formula III are converted into compounds of Formula IV mostconveniently by reacting the former with ethylene oxide in the presenceof an aprotic Lewis acid such as a Friedel-Crafts catalyst, e.g., borontrifiuoride, stannic chloride, titanium tetrachloride, and aluminumchloride. A most preferred catalytic material for the purposes of thisreaction is aluminum chloride. Conventional solvents useful inFriedel-Crafts type reactions may be employed. A most preferred class ofsolvent include the aromatic hydrocarbons such as for example, benzene,xylene, toluene etc. The reaction may be conducted at a temperature inthe range of from about 045 C., most preferably in the range of fromabout 30-40 C. However, even higher temperatures may 'be utilizedproviding that the system be placed under pressure so as to prevent lossof the volatile ethylene oxide.

It should be noted that when R and/or R have the meaning amino in thefinal compound of Formula I above, it is preferred that such compoundsbe prepared by reduction of the corresponding R and/or R nitro groups ina manner known in the art subsequent to the ethylene oxide step. This isdue to the fact that amino substituents in compounds of the Formula IIIwould react with the ethylene oxide reagent. Thus, subsequent conversionof the nitro group to the amino group after the ethylene oxide step isindicated.

Transformation of compounds of Formula IV into corresponding compoundsof Formula II will, of course, proceed in alternative fashion, dependingupon the nature of leaving group A. In the case where leaving group A isone of the three enumerated halogens, a halogenating agent can beutilized in this reaction. Suitable halogenating agents include for thecase of chlorine, thionyl chloride, phosphorus trichloride, phosphoruspentachloride, etc. In the bromine embodiment, hydrogen bromide orphosphorus tribromide are suitable reagents whereas hydrogen iodide isthe reagent of preference for the iodine embodiment. The tosyl or mesylhalides form a preferred group of reagents useful for insertion of thetosyloxy or mesyloxy groups as members of leaving group A. In thereaction of compounds of Formula IV with the respective leaving groupreagents, any solvent inert to the reactants may be utilized. Examplesof such solvents include halogenated hydrocarbons such as methylenechloride, chloroform, etc. and the aromatic hydrocarbons such asbenzene, toluene, xylene, etc. A temperature in the range of from C. to200 C. preferably from 0 C. to boiling point of the reaction medium isused. It is also possible to utilize the leaving group reagent in excessas the solvent medium. In such instances a temperature in the range offrom about 0 to 150 C. may be employed.

In another process embodiment of this invention compounds of Formula Imay be prepared by the eyclization of compounds of the following formulawhere R R R and A are as above.

This cyclization reaction is conducted in the presence of a base such asa carbonate, e.g., potassium or sodium carbonate, or an alkali oralkaline earth hydroxide, etc. A useful solvent medium for this reactioncomprises an aqueous lower alkanol, e.g., aqueous ethanol. Additionally,the reaction medium may contain an organic base, such as pyridine ortriet hylamine which serve as both solvents and added bases. Thereaction conditions employed will be the same as previously describedfor the preparation of compounds of Formula I from compounds of FormulaII.

The compounds of Formula V above may be conveniently prepared by firstreacting hydroxylamine or an acid salt thereof, e.g., hydroxylaminehydrochloride with a compound of Formula IV so as to produce an oxime ofthefollowing formula i t N-CH:CH2OH R1 where R R and R are as above;

and then transforming the above oxime into the corresponding compoundsof Formula V in the same manner previously described for the conversionof compounds of Formula IV into the compounds of Formula II, such as forexample in a preferred embodiment where A is chloro, by the use ofthionyl chloride at reflux in a halogenated solvent, e.g., methylenechloride.

Compounds of Formulae V and VI are novel inter-mediates and as such areconsidered to be a part of the present invention.

Compounds of the following formula Ilia N wherein R R and R are as aboveare known to be valuable therapeutic agents and are useful as musclerelaxants, sedatives and anti-convulsants.

Compounds of Formula I are readily converted into compounds of FormulaVII by a reduction step whereby the oxygen atom on the 4-nitrogen isreductive'ly eliminated.

The aforesaid reduction reaction may be carried out catalytically in thepresence of hydrogen utilizing conventional hydrogenation catalysts suchas Raney-nickel for this purpose. In a more preferable embodiment,especially when substituents R and/or R encompass groups sensitive tocatalytic reduction, a chemical reducing agent such as phosphorustrichloride is employed. In the latter embodiment, a temperature in therange of from about C. to the reflux temperature of the reaction mediumis utilized. Conventional inert solvents for this reduction step can beemployed. Suitable solvents include, for example, the halogenatedhydrocarbons such as methylene chloride, chloroform, etc. or thearomatic hydrocarbons such as, for example, benzene, toluene, xylene,etc.

The following examples are illustrative but not limitative of theinvention. Other embodiments will be obvious to those skilled in the artand are comprehended by the scope of the invention. All temperatures arestated in degrees centigrade, and all melting points are corrected.

EXAMPLE 1 Conversion of chloro 2 (2-chloroethylamino)benzo phenone into7 chloro 2,3 dihydro-l-methyl-S- phenyl-1H-1,4--benzodiazepine 4-oxideTo a solution of 5-chloro-2-(2-chloroethyla-mino)benzophenone (2 gm.,6.5 mm.) in ethanol (20 ml.) was added a solution of hydroxylaminehydrochloride (4.52 gm., 65 mm.) and potassium carbonate (4.14 gm., 30mm.) in water ml.). The mixture was stirred and refluxed for 24 hours,and was then concentrated in vacuo, and diluted with water. The mixturewas made basic with sodium hydroxide solution, and the crude product wasrecovered by extraction with methylene chloride. Evaporation of theextract gave a yellow foam (1.82 gm.), which was dissolved in benzene,and purified by filtration through a column of Woelm activity IIIneutral alumina (18 gm.). Evaporation of the benzene eluate afi'ordednearly pure product as a yellow partly crystalline gum. This materialbecame completely crystalline when triturated with ether orether-hexane, giving the above-titled product as pale yellow prisms,M.P. 165--167 C.

EXAMPLE 2 Preparation of S-chloro-Z- (2-hydroxyethylmethylamino)benzophenone To a stirred suspension of anhydrous aluminum chloride(79.8 gm., 0.6 mols.) in dry benzene (200 ml.) Was added a solution of2-methylamino-5-chlorobenzophenone (73.7 gm., 0.3 mols.) in dry benzene(200 ml.) during 1.5 hours. The temperature rose slowly to 40 C. Themixture was allowed to cool spontaneously to 30-35 C., and a solution ofethylene oxide (44.0 gm., 1.0 mols.) in dry benzene (100 ml.) was addeddropwise during 1.5 hours, maintaining the temperature at 3035 C. byusing a water-bath. The progress of the reaction was followed by thinlayer chromatography (TLC) of samples on plates of silica gel F254(Merck), which were developed with ethyl acetate, and examined undershortwave UV light. To complete the conversion two further portions ofethylene oxide were added as previously, with periods of several hoursin between additions. The reaction mixture was then poured onto ice (1.5kg.), followed by addition of concentrated hydrochloric acid (300 ml.).The aqueous acid layer was separated, and the organic layer was furtherextracted with 3 N-hydrochloric acid (5x 200 ml.). The combined aqueousextracts were cooled, made basic with 40% (w./v.) sodium hydroxidesolution, and extracted with methylene chloride. The extract was washedwith saturated aqueous sodium chloride, and dried over sodium sulfate.Evaporation afforded the crude product as a red oil, which was dissolvedin benzene and filtered through a column of Woelm activity I neutralalumina (850 gm.). The benzene eluate was discarded; the purifiedproduct was obtained by elution of the column with methylene chloride,and evaporation of the eluate, to give5-chloro-2-(2-hydroxyethylmethylamino) benzophenone as a yellow oilwhich was identical with an authentic sample by comparison of TLC and IRdata.

EXAMPLE 3 Preparation of 5-chloro-2-(2-chloroethylmethylamino)benzophenone A solution of 5-chloro-2-(2-hydroxyethylmethylamino)benzophenone (23.3 gm., 80.3 mm.) and pyridine (2 drops) in methylenechloride (200 ml.) was stirred and treated dropwise with a solution ofthionyl chloride (14.4 ml., 23.8 gm., 200 mm.) in methylene chlorideml.) during 1.5 hours, followed by refluxing for 2 hours, withprotection from atmospheric moisture. The mixture was evaporated invacuo and excess thionyl chloride removed by co-distillation withmethylene chloride. Ice-water (200 ml.) and 3 N-sodium hydroxidesolution ml.) were added, and the crude product was recovered byextraction with methylene chloride. The extract was washed withsaturated aqueous sodium chloride, dried over sodium sulfate, andevaporated in vacuo to give product as a dark red oil. This wasdissolved in benzene, and purified by filtration through a column ofWoelm activity I neutral alumina (230 gm.). Evaporation of the benzeneeluate gave pure product as a yellow oil identical with an authenticsample by comparison of TLC and IR data.

EXAMPLE 4 Deoxygenation of7-chloro-2,3-dihydro-1-methyl-5-phenyl-lH-l,4-benzodiazepine 4-oxide to7-chloro-2,3-dihydrol-methyl-S-phenyl- 1H, 1,4-benzodiazepine A solutionof 7-chloro-2,3-dihydro-l-methyl-S-phenyl- 1H-1,4-benzodiazepine 4 oxide(1 gm., 3.48 mm.) in methylene chloride (40 ml.) was treated withphosphorus trichloride (1 ml., 1.57 gm., 11.5 mm.), and refluxed for 0.5hr., with protection from atmospheric moisture. The cooled reactionmixture was poured onto ice, and was then made basic with sodiumhydroxide. Evaporation of the washed extracts gave V as a light browngum which was converted into the monohydrochloride by treatment withexcess methanolic hydrogen chloride, and precipitation with ether. Thenearly pure 7-chloro-2,3-dihydro-1-methyl-S-phenyl-IH-1,4-benzodiazepine hydrochloride was thus obtained asorange prisms, M.P. 248-250 C. (sealed tube).

EXAMPLE 5 Preparation of 2-[2-benzoyl-4-chloro-N-methylanilino]ethanoloxime A solution of 5.9 g. (20.4 mmols.) of 5-chloro-2-(2-hydroxyethylrnethylamino)benzophenone, 2.8 g. (41 mmols.) ofhydroxylamine hydrochloride and 45 ml. of pyridine was refluxed withprotection from moisture for 22 hours. After cooling, most of thepyridine was removed in vacuo, the residue poured into water andextracted with methylene chloride. The methylene chloride extracts werewashed with water, dried (MgSO and concentrated and allowed to stand at0 to induce crystallization. The above-titled crude product wasrecrystallized from benzene:pentane to give 3.3 g. (53 percent) of whitetan crystals, M.P. 109.5111.5 C. The analytical sample was prepared byrecrystallization from the same solvent, M.P. 113-114 C.

EXAMPLE 6 Preparation of 7-chloro-2,3-dihydro-l-methyl-S-phenyl-1H-1,4-benzodiazepine 4 oxide from 2-(2-benzoyl-4-chloro-N-methylanilino)ethanol oxime A solution of2-(2-benzoyl-4-chloro-N-methylanilino) ethanol oxime (25 gm., 180.3 mm.)and pyridine (2 drops) in methylene chloride (200 ml.) was stirred andtreated dropwise with a solution of thionyl chloride (14.4 ml., 23.8gm., 200 mm.) in methylene chloride during 1.5 hours, followed byrefluxing for 2 hours with protection from atmospheric moisture. Themoisture was evaporated in 'vacuo and excess thionyl chloride wasremoved by co-distillation with methylene chloride. ice-water (200 ml.)and 3 N sodium hydroxide solution (100 ml.) were added and the crude2-(2-benzoyl-4-chloroN-methylanilino)ethyl chloride oxime product wasrecovered by extraction with methylene chloride. The extract was washedwith saturated aqueous sodium chloride, dried over sodium sulfate andevaporated in vacuo..The residue was dissolved in benzene and purifiedby filtration through a column of Woelm activity I neutral alumina (230gm.). Evaporation of the benzene gave the pure chloro-oxime.

To a solution of 2-(2-benzoyl-4-chloro-N-methylanilino) ethyl chlorideoxime (2.14 gm., 6.5 mm.) in ethanol (20 ml.) was added a solution ofpotassium carbonate (4.14 gm., 30 mm.) in water ml.). The mixture wasstirred and refluxed for 24 hours, and was then concentrated in vacuo,and diluted with water. The mixture was made basic with sodium hydroxidesolution and the crude product was recovered by extraction withmethylene chloride. The residue obtained after evaporation of thesolvent was dissolved in benzene, and purified by filtration of Woelmactivity III neutral alumina (18 gnu). Evaporation of the benzene eluateafforded a nearly pure product as a yellow crystalline gum. Thismaterial became completely crystalline when triturated with ether oretherhexane, giving 7-chloro-2,3-dihydro-l-methyl-S-phenyl-1H-l,4-benzodiazepine 4-oxide as pale yellow prisms, M.P. 165-167 C.

We claim:

1. A compound of the formula II NOHzCH2A wherein R and R each areselected from the group consisting of hydrogen, halogen,trifiuoromethyl, nitro, amino, lower alkanoyl-amino, lower alkylthio,lower alkyl sulfonyl, lower alkylsulfinyl, lower alkoxy, hydroxy, loweralkyl, cyano, carboxy, carbo-lower alkoxy, carbamyl, and di-loweralkylamino; and R is selected from the group consisting of hydrogen,lower alkyl, lower alkenyl and lower alkanoyl; and A is a leaving groupselected from the group consisting of chlorine, bromine, iodine,tosyloxy and mesyloxy.

2. 2-(2 benzoyl 4 chloro-N-methyl-anilino) ethyl chloride oxime.

References Cited UNITED STATES PATENTS 3,465,038 9/ 1969 Dolan 2605-66 A3,523,972 8/ 1970 Field et al. 260-566 A 3,531,467 9/1970 Archer et a1.260-566 A X 3,420,817 1/ 1969 Stempel et a1. 260-566 A X JOSEPH E.EVANS, Primary Examiner G. A. SCHWARTZ, Assistant Examiner US. Cl. X.R.

260456 A, 465 E, 465 D, 470, 471 R, 471 C, 518 R, 518 A, 519, 558 A, 558S, 559 A, 559 T, 562 P, 573, 999; 424-244

